Malignant melanoma is the most lethal form of skin cancer. Although preclinical studies have shown that n-3 polyunsaturated fatty acids (PUFAs) are beneficial for prevention of melanoma, the molecular mechanisms underlying the protective effects of n‑3 PUFAs on melanoma remain largely unknown. In the present study, endogenously increased levels of n-3 PUFAs in the tumor tissues of omega‑3 fatty acid desaturase (fat‑1) transgenic mice was associated with a reduction in the growth rate of melanoma xenografts. This reduction in tumor growth in fat‑1 mice compared with wild‑type controls may have been associated, in part, to the: i) Increased expression of E‑cadherin and the reduced expression of its transcriptional repressors, the zinc finger E‑box binding homeobox 1 and snail family transcriptional repressor 1; ii) significant repression of the epidermal growth factor receptor/Akt/β‑catenin signaling pathway; and iii) formation of significant levels of n‑3 PUFA‑derived lipid mediators, particularly resolvin D2 and E1, maresin 1 and 15‑hydroxyeicosapentaenoic acid. In addition, vitamin E administration counteracted n‑3 PUFA‑induced lipid peroxidation and enhanced the antitumor effect of n‑3 PUFAs, which suggests that the protective role of n‑3 PUFAs against melanoma is not mediated by n‑3 PUFAs‑induced lipid peroxidation. These results highlight a potential role of n‑3 PUFAs supplementation for the chemoprevention of melanoma in high‑risk individuals, and as a putative adjuvant agent in the treatment of malignant melanoma.